Microfluidic devices (microdevices) hold great promise for many fields of use, including chemical analysis or clinical diagnostics. The small size of microdevices allows for the analysis of minute quantities of fluids or samples, which is an important advantage when the fluids or samples are expensive or difficult to obtain. To enhance the functionality of sample analysis devices, it has been proposed that preparation, separation and detection compartments be integrated on such devices. Microfluidic technologies are generally described, for example, in U.S. Pat. Nos. 5,500,071 to Kaltenbach et al., U.S. Pat. No. 5,571,410 to Swedberg et al., and U.S. Pat. No. 5,645,702 to Witt et al.
Since many microfabricated devices have a relatively simple construction, they are in theory inexpensive to manufacture. Nevertheless, the production of such devices presents various challenges. For example, the flow characteristics of fluids in the small flow channels of a microfabricated device may differ from the flow characteristics of fluids in larger devices, as surface effects come to predominate and regions of bulk flow become proportionately smaller. In particular, the implementation of fluid flow control and fluid mixing in microdevices presents unique challenges.
With respect to fluid flow control, for example, conventional wisdom dictates that valve structures, which control flow of fluids in bulk, are not easily adaptable for use in microfluidic devices due to the predominance of surface effects. Accordingly, various patents describe valve technologies for use in microdevices. See, e.g., U.S. Pat. Nos. 4,869,282 to Sittler et al., U.S. Pat. No. 5,333,831 to Barth et al., U.S. Pat. No. 5,368,704 to Madou et al., U.S. Pat. No. 5,417,235 Wise et al., U.S. Pat. No. 5,725,017 to Elsberry et al., U.S. Pat. No. 5,771,902 to Lee et al., U.S. Pat. No. 5,819,794 to Anderson, U.S. Pat. No. 5,927,325 to Bensaoula et al., U.S. Pat. No. 5,964,239 to Loux et al., and U.S. Pat. No. 6,102,068 to Higdon et al. Many of these valve technologies, however, are complex in construction and are incapable of the fast response times required in certain biomolecule analysis applications due to an excess of “dead space,” i.e., unused and unnecessary space within the microdevice.
A simplified valve structure for controlling fluid flow has been proposed in U.S. Patent Application Publication No. 2003/0015682 to Killeen et al. This published application describes a microdevice comprising a substrate and a cover plate, each having a substantially planar contact surface and a fluid-transporting feature associated therewith. The substrate contact surface is positioned in slidable and fluid-tight contact with the cover plate contact surface to allow for controllable alignment between the fluid-transporting features. As a result, fluid communication is provided between the fluid-transporting features through a sliding and/or rotational motion. In addition, the microdevice may be used to form controllable and/or alignment-dependent variable-length flow paths. The simplified valve structure may be used in microdevices for component separation such as those described in U.S. Patent Application Publication No. 2003/0017609 to Yin et al.
With respect to fluid-mixing technologies in the context of microdevices, they may be categorized as active or passive. Active techniques typically involve use of an exogenous mechanism to effect fluid mixing by introducing local disturbances or instabilities in fluids. For example localized disturbances or instabilities may be introduced via cavitation action through the use of ultrasonic mixing (see Yasuda (2000), “Non-Destructive Mixing, Concentration, Fractionation and Separation of μm-sized Particles in Liquid by Ultrasound,” Proc. Micro Total Analysis Systems 2000 (μTAS 2000 Symposium), Enschede, The Netherlands, 14-18 May 2000, pp.343-346). Other examples of active mixing techniques include, but are not limited to, order-changing micromixing techniques (see U.S. Pat. No. 6,331,073 to Chung), magnetohydrodynamic-driven mixing (see U.S. Pat. No. 6,146,103 to Lee et al.), electrokinetic mixing (see Branebjerg, et al. (1996), “Fast Mixing by Lamination,” Proc. MEMS-96, San Diego, USA, Feb. 11-15, 1996, pp. 441-446 and U.S. Patent Application Publication No. 2002/0125134 to Santiago et al.), active flow disturbance (see Woias et al. (2000), “An Active Silicon Micromixer for μTAS Applications,” Proc. Micro Total Analysis Systems 2000 (μTAS 2000 Symposium), Enschede, The Netherlands, 14-18 May 2000, pp.277-282), and bubble-pulsed double-dipole flow field mixing (see U.S. Pat. No. 6,065,864 to Evans et al.).
Passive techniques, on the other hand, typically rely more on diffusion and laminar flow streams to effect mixing. Examples of passive mixers include, but are not limited to, simple diffusion (see, e.g., U.S. patent application Ser. No. 10/085,598, entitled “Mobile Phase Gradient Generation Microfluidic Device, filed Feb. 26, 2002, inventors Yin, Killeen, and Sobek), lamination diffusion (see Branebjerg et al, “Fast Mixing by Lamination,” Proc. MEMS-96, San Diego, USA, Feb. 11-15, 1996, pp. 441-446; U.S. Patent Application Publication No. 2002/0057627 to Schubert et al.; U.S. Pat. No. 6,264,900 to Schubert et al.; U.S. Pat. No. 6,082,891 Schubert et al.; and U.S. Pat. No. 5,921,678 Desai et al.), plume injection (see Miyake et al. (1993), “Micro Mixer with Fast Diffusion,” Proc. MEMS-93, Fort Lauderdale, USA, Feb. 7-10, 1993, pp. 248-253, chaotic mixing (see Stremler et al. (2000), “Chaotic Mixing in Microfluidic Systems,” Tech. Digest of Solid-State Sensor and Actuator Workshop, Hilton Head Island, USA, Jun. 4-8, 2000, pp. 187-190; Liu et al. (2001), “Plastic In-line Chaotic Micromixer for Biological Applications,” Proc. Micro Total Analysis Systems 2001 (μTAS 2001 Symposium), Monterey, USA, 21-25 Oct. 2001, pp. 163-164; and U.S. Pat. No. 6,331,072 to Schierholz et al.), “Coanda” effect mixing (see Hong et al. (2001), “A Novel In-plane Passive Micromixer Using Coanda Effect,” Proc. Micro Total Analysis Systems 2001 (μTAS 2001 Symposium), Monterey, USA, 21-25 Oct. 2001, pp.31-33), and vortex mixing (see Böhm (2001), “A Rapid Vortex Micromixer for Studying High-Speed Chemical Reactions,” Proc. Micro Total Analysis Systems 2001 (μTAS 2001 Symposium), Monterey, USA, 21-25 Oct. 2001, pp. 25-27; and U.S. Application Patent Publication No. 2001/0048900 to Bardell et al.).
The mixing techniques discussed above suffer from a number of drawbacks. Like the conventional valve technology described above, the active mixing technologies are usually complex in construction. In addition, both active and passive mixing technologies ordinarily require dedicated regions within a microdevice, which tends to increase the size and complexity of the microdevice. For example, high-throughput microfluidic applications may require use of dedicated channels in a microdevice when passive mixing is used so as to provide for the sufficiently high diffusion rates needed to carry out the high-throughput applications.
Thus, akin to the need for improved and simplified fluid control technology in the microfluidic arts, there is a corresponding need for an improved and simplified mixing structure. The invention overcomes the above-mentioned disadvantages of the prior art by providing such improved mixing devices and methods, which are adaptable for use with microdevice technologies, particularly those that employ valve assembly technologies such as those described in U.S. Patent Application Publication Nos. 2003/0015682 to Killeen et al. and 2003/0017609 Yin et al.